Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

David Rombaut, Carine Lefèvre, Tony Rached, Sabrina Bondu, Anne Letessier, Raphael M. Mangione, Batoul Farhat, Auriane Lesieur-Pasquier, Daisy Castillo-Guzman, Ismael Boussaid, Chloé Friedrich, Aurore Tourville, Magali De Carvalho, Françoise Levavasseur, Marjorie Leduc, Morgane Le Gall, Sarah Battault, Marie Temple, Alexandre Houy, Didier Bouscary, Lise Willems, Sophie Park, Sophie Raynaud, Thomas Cluzeau, Emmanuelle Clappier, Pierre Fenaux, Lionel Adès, Raphael Margueron, Michel Wassef, Samar Alsafadi, Nicolas Chapuis, Olivier Kosmider, Eric Solary, Angelos Constantinou, Marc-Henri Stern, Nathalie Droin, Benoit Palancade, Benoit Miotto, Frédéric Chédin and Michaela Fontenay ()
Additional contact information
David Rombaut: Institut Cochin
Carine Lefèvre: Institut Cochin
Tony Rached: Institut Cochin
Sabrina Bondu: Institut Cochin
Anne Letessier: Institut Cochin
Raphael M. Mangione: Institut Jacques Monod
Batoul Farhat: Institut Cochin
Auriane Lesieur-Pasquier: Institut Cochin
Daisy Castillo-Guzman: University of California
Ismael Boussaid: Institut Cochin
Chloé Friedrich: Institut Cochin
Aurore Tourville: Institut Cochin
Magali De Carvalho: Institut Cochin
Françoise Levavasseur: Institut Cochin
Marjorie Leduc: Institut Cochin
Morgane Le Gall: Institut Cochin
Sarah Battault: Institut Cochin
Marie Temple: Laboratory of Hematology
Alexandre Houy: Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer
Didier Bouscary: Institut Cochin
Lise Willems: Institut Cochin
Sophie Park: Centre Hospitalier Universitaire, Université de Grenoble Alpes
Sophie Raynaud: Université Côte d’Azur, Centre Hospitalier Universitaire
Thomas Cluzeau: Université Côte d’Azur, Centre Hospitalier Universitaire
Emmanuelle Clappier: Laboratory of Hematology
Pierre Fenaux: Service Hématologie Séniors
Lionel Adès: Service Hématologie Séniors
Raphael Margueron: Paris Sciences Lettres Research University, Sorbonne University, INSERM U934
Michel Wassef: Paris Sciences Lettres Research University, Sorbonne University, INSERM U934
Samar Alsafadi: Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer
Nicolas Chapuis: Institut Cochin
Olivier Kosmider: Institut Cochin
Eric Solary: INSERM 1287, Université Paris Saclay
Angelos Constantinou: Université de Montpellier
Marc-Henri Stern: Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer
Nathalie Droin: INSERM 1287, Université Paris Saclay
Benoit Palancade: Institut Jacques Monod
Benoit Miotto: Institut Cochin
Frédéric Chédin: University of California
Michaela Fontenay: Institut Cochin

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46547-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46547-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46547-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().